Immunogenicity and Protective Efficacy of a SARS-CoV-2 mRNA Vaccine Encoding Secreted Non-Stabilized Spike Protein in Mice

Prompetchara, Eakachai; Ketloy, Chutitorn; Alameh, Mohamad-Gabriel; Tarakhet, Kittipan; Kaewpang, Papatsara; Yostrerat, Nongnaphat; Pitakpolrat, Patrawadee; Buranapraditkun, Supranee; Manopwisedcharoen, Suwimon; Thitithanyanont, Arunee; Jongkaewwattana, Anan; Hunsawong, Taweewan; Im-Erbsin, Rawiwan; Reed, Matthew; Wijagkanalan, Wassana; Patarakul, Kanitha; Palaga, Tanapat; Lam, Kieu; Heyes, James; Weissman, Drew; Ruxrungtham, Kiat

doi:10.1101/2022.09.07.506878

Cited by 6 publications

(10 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ChulaCov19 was designed in Thailand and manufactured in North America for early clinical trials, in parallel with large-scale production capacity development in Thailand. In rodent and macaques, ChulaCov19 elicited strong B-and T-cell responses 3 .…”

Section: Pseudovirus Neutralization Tests (Psvnt-50)mentioning

confidence: 99%

Safety and immunogenicity of a prefusion non-stabilized spike protein mRNA COVID-19 vaccine: a phase I trial

Gatechompol

Kittanamongkolchai²,

Ketloy³

et al. 2022

Nat Microbiol

Self Cite

View full text Add to dashboard Cite

Effective mRNA SARS-CoV-2 vaccines are available but need to be stored in freezers, limiting their use to countries that have appropriate storage capacity. ChulaCov19 is a prefusion non-stabilized SARS-CoV-2 spike-protein-encoding, nucleoside-modified mRNA, lipid nanoparticle encapsulated vaccine that we report to be stable when stored at 2-8 °C for up to 3 months. Here we report safety and immunogenicity data from a phase I open-label, dose escalation, first-in-human trial of the ChulaCov19 vaccine (NCT04566276). Seventy-two eligible volunteers, 36 of whom were aged 18-55 (adults) and 36 aged 56-75 (elderly), were enroled. Two doses of vaccine were administered 21 d apart at 10, 25 or 50 μg per dose (12 per group). The primary outcome was safety and the secondary outcome was immunogenicity. All three dosages of ChulaCov19 were well tolerated and elicited robust dose-dependent and age-dependent B-and T-cell responses. Transient mild/ moderate injection site pain, fever, chills, fatigue and headache were more common after the second dose. Four weeks after the second dose, in the adult cohort, MicroVNT-50 geometric mean titre against wild-type SARS-CoV-2 was 848 (95% CI, 483-1,489), 736 (459-1,183) and 1,140 (854-1,522) IU ml −1 at 10, 25 and 50 μg doses, respectively, versus 285 (196-413) IU ml −1 for human convalescent sera. All dose levels elicited 100% seroconversion, with geometric mean titre ratios 4-8-fold higher than for human convalescent sera (P < 0.01), and high IFNγ spot-forming cells per million peripheral blood mononuclear cells. The 50 μg dose induced better cross-neutralization against Alpha, Beta, Gamma and Delta variants than lower doses. ChulaCov19 at 50 μg is well tolerated and elicited higher neutralizing antibodies than human convalescent sera, with strong T-cell responses. These antibodies cross-neutralized four variants of concern. ChulaCov19 has proceeded to phase 2 clinical trials. We conclude that the mRNA vaccine expressing a prefusion non-stabilized spike protein is safe and highly immunogenic.More than 10 billion doses of COVID-19 vaccines have been administered worldwide but only 10% of those living in low-income countries have received at least one dose (8 February 2022) 1 . Among approved vaccines, mRNA vaccines have the highest efficacy 2 . Building capacity to develop and manufacture mRNA vaccines in low-to middle-income countries (LMIC) is important for the current and future pandemics.

show abstract

Section: Pseudovirus Neutralization Tests (Psvnt-50)mentioning

confidence: 99%

Safety and immunogenicity of a prefusion non-stabilized spike protein mRNA COVID-19 vaccine: a phase I trial

Gatechompol

Kittanamongkolchai²,

Ketloy³

et al. 2022

Nat Microbiol

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast, dipeptidyl peptidase (DPP)-4 and aminopeptidase N (APN) receptors of other CoVs are not used by SARS-CoV-2 (Zhou, P et al, 2020). DPP-4 is a particular receptor for MERS-CoV (Prompetchara et al, 2020;Wan et al, 2020) while SARS-CoV-2 and SARS-CoV recognize ACE2. In addition, the spikes, RBDs, and RBM (receptor binding motif) of human MERS-CoV and bat MERS-like Covs have a lower similarity in their sequencing proteins (Wan et al, 2020).…”

Section: A Origin Of Sars-cov-2 and Its Genetic Featuresmentioning

confidence: 99%

“…Additionally, the severity of COVID-19 and patient death associated with those changing levels of the neutrophils and lymphocytes (Prompetchara et al, 2020). Titers of IgG and IgM have recorded an elevated level in the serum of SARS-CoV-2 patients (Zhou,P et al, 2020).…”

Section: Immune Responsesmentioning

confidence: 99%

“…The ongoing reported common symptoms of COVID-19 are fever, dry cough, throat sore, dyspnea, and fatigue (Cheng et al, 2020;Huang et al, 2020;Wang et al, 2020). The incubation period of the disease ranges from 2 to 14 days, however, 80% of the patients had mild or asymptomatic illness while 15 % and 5% of the patients had exhibited sever and critical cases respectively (Prompetchara et al, 2020;Rokni et al,2020). Asymptomatic persons have a role in spreading SARS-CoV-2, yet they suffer from the symptoms 14 days after the viral infection (Al-Tawfiq, 2020;Rothe et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mini-Review: SARS-CoV-2 and COVID-19

Alhasan¹,

Al-Saidy²

2021

jsci

View full text Add to dashboard Cite

On 31 December 2019, the cases of pneumonia caused by unknown etiology had emerged. These cases were reported in Wuhan city, Hubei Province of China. Chinese authorities identified the causative agent and announced to be a novel coronavirus. The tentative name of disease is COVID-19, abbreviating of coronavirus disease-19. The incubation period of the disease ranges from 2 to 14 days, however, 80% of the patients have mild or asymptomatic illness while 15 % and 5% of the patients had exhibited sever and critical cases respectively. The etiology of COVID-19 was known as SARS-CoV-2 and belongs to betacoranviruse as reported by the International Committee on Taxonomy of Viruses (ICTV) especially Coronaviridae Study Group (CSG). In addition, this virus is currently believed to be within bat-coronaviruses besides it possesses a close relationship with SARS-CoV more than MERS-CoV. Although, the majority of the diagnosed patients had symptoms, there were asymptomatic persons who can spread the SARS-CoV-2. Upon the emergence of worldwide distribution of this virus, the WHO had declared it as a global outbreak and pandemic. Unfortunately, at present time, there are neither vaccine and nor an approved COVID-19 specific drug against SARS-CoV-2. One of the remarkable pathogenesis mechanistic step of this virus is taking possession of the affinity to angiotensin-converting enzyme 2 (ACE2). This mini-review summarizes the origin and molecular identification of the virus as well as the host immune responses. SARS-CoV-2 , COVID-19, ACE2, origin

show abstract

“…Moreover, cryo-electron microscopy studies showed the overall structures of S with or without the diproline substitutions to be highly similar with an overall root mean square deviation of 0.54( 22 ). In mice, the 2P substitutions were not required for potent immunogenicity of SARS-CoV-2 spike ( 23 ). It should also be noted that the Oxford-AstraZeneca COVID-19 vaccine developers chose to express from an adenoviral vector spike without the 2P substitutions for their vaccine ( 24, 25 ).…”

Section: Introductionmentioning

confidence: 99%

Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates

Malewana,

Stalls,

May

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs.One Sentence SummaryNon-stabilized SARS-CoV-2 Spike mRNA vaccination activated B cells that target either conserved epitopes on SARS-CoV-2 Omicron variants of concern, or cross-neutralizing epitopes on pre-emergent Sarbecoviruses.

show abstract

Immunogenicity and Protective Efficacy of a SARS-CoV-2 mRNA Vaccine Encoding Secreted Non-Stabilized Spike Protein in Mice

Cited by 6 publications

References 44 publications

Safety and immunogenicity of a prefusion non-stabilized spike protein mRNA COVID-19 vaccine: a phase I trial

Safety and immunogenicity of a prefusion non-stabilized spike protein mRNA COVID-19 vaccine: a phase I trial

Mini-Review: SARS-CoV-2 and COVID-19

Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates

Contact Info

Product

Resources

About